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We present herein the synthesis in good yields of two series of highly functionalized thiazolidinone derivatives from the reactions of various 4-phenyl-3-thio-semicarbazones with ethyl 2-bromoacetate and diethyl acetylenedicarboxylate, respectively.

Thiosemicarbazones are a class of small molecules that have been evaluated over the last 50 years as antiviral [1] and as antitumoral agents [2,3,4], in addition to their antiparasitic and bacterial action against Trypanasoma cruzi [5,6,7] and Toxoplasma gondii and several bacterial strains [8]. Thiosemicarbazones have been used as intermediates for a great variety of heterocyclic products, such as thiazolidinones, thiohydantoins, thioxopyrimidinediones. It is reported that thiazolidinones exhibit antibacterial [9], antifungal [10], anticonvulsant [11], antitubercular [12], anti-inflammatory [13], antihistaminic [14,15], cardiovascular [16] and anti-HIV [17] activities. As part of our research program on new bioactive compounds [18,19,20,21,22], we report herein an efficient synthesis of some new highly functionalized thiazolidinones derived from 4-phenyl-3-thiosemicarbazones.

2. Results and Discussion

The starting materials, 4-phenyl-3-thiosemicarbazones 4a–h, were synthesized in two steps. The first step was the preparation of 4-phenyl thiosemicarbazide (2) in 86% yield from phenyl isothiocyanate (1) and hydrazine hydrate in ethanol at room temperature [23] (Scheme 1).

molecules-19-03068-scheme1_Scheme 1Scheme 1

Preparation of 4-phenyl-3-thiosemicarbazide (2).

The reaction of 4-phenyl-3-thiosemicarbazide (2) with various aromatic aldehydes 3a–h in the presence of few drops of acetic acid at 85 °C for 1–3 h, led to the corresponding 4-phenyl-3-thiosemicarbazone derivatives 4a–h in good yields (70%–93%), as shown in Scheme 2 and Table 1.

molecules-19-03068-scheme2_Scheme 2Scheme 2

Preparation of 4-phenyl-3-thiosemicarbazones 4a–h.

The most characteristic signals in the 1H-NMR spectrum of this family of thiosemicarbazones were those corresponding to the CH=N and N-H protons. 1H-NMR studies showed the CH=N protons in the 7.86–8.62 ppm range, whereas thiourea N-H protons are found in the 9.13–11.78 ppm interval for N-H adjacent to the monosubstituted phenyl ring and for the N-H adjacent to the CH=N moiety, respectively. All of the synthesized compounds were in the E-configuration, which was confirmed using 1H-NMR spectroscopy, as the signal of the NH group was in the 9–12 ppm range, in comparison to the Z-isomer, which possesses a characteristic NH signal in the 14–15 ppm range [24].

molecules-19-03068-t001_Table 1Table 1

Reaction of 2 with various aromatic aldehydes 3a–h.

Carbonyl compound

Product

Product number

Reaction time (h)

Yield (%)

4a

1

70

4b

3

90

4c

2

93

4d

1

90

4e

1

91

4f

2

89

4g

2

91

4h

1

89

The reaction of various 4-phenyl thiosemicarbazones 4a–h with ethyl 2-bromoacetate (5) as cyclizing reagent in boiling absolute ethanol containing three equivalents of anhydrous sodium acetate during 1–3 h, afforded to the thiazolidin-4-ones 6a–h in good yields (68%–91%) as shown in Scheme 3 and Table 2.

molecules-19-03068-scheme3_Scheme 3Scheme 3

Preparation of thiazolidinones 6a–h.

molecules-19-03068-t002_Table 2Table 2

Reactions of 4a–h with ethyl 2-bromoacetate (5).

Compound

Product

Product number

Reaction time (h)

Yield (%)

4a

6a

1

91

4b

6b

3

68

4c

6c

3

82

4d

6d

2

86

4e

6e

2

80

4f

6f

3

89

4g

6g

3

90

4h

6h

2

88

The structures of all new compounds 6a–h were established by analysis of their IR, 1H-NMR and 13C-NMR data. The IR spectra of the thiazolidin-4-ones 6a–h showed absorption bands at about 1,734–1,716 cm−1 characteristic of (amide group) C=O stretching vibrations. Further support was obtained from the 1H-NMR spectra, where it did not display signs of the 4-phenyl-3-thiosemicarbazone (NH) protons. On the other hand, the 1H-NMR spectra exhibited resonances assigned to the SCH2 group of the thiazolidine ring appearing as a singlet at 3.97–4.10 ppm due to the methylene protons. The CH=N protons in these structures were observed in the 7.67–8.57 ppm region. The formation of thiazolidinones 6a–h ocurred in two steps: the first step of this reaction is thought to be S-alkylation of thiosemicarbazide in its thiol form due to the sodium acetate used. Second step involved loss of ethanol to give the thiazolidin-4-one. The electronic and steric properties of the substituent at the 4-position of the thiosemicarbazones seems to be a determining factor for the formation of the thiazolidinone ring. Previous reports on these types of compounds reveal a small substituent such as phenyl or alkyl leads to a 4-thiazolidinone ring by loss of ethanol [25].

The next cyclization reaction of 4-phenyl-3-thiosemicarbazones derivatives 4a–h was conducted using diethyl acetylenedicarboxylate in methanol for 1 h [26], as shown in Scheme 4 and Table 3. In this reaction both of the sulfur group and the amino group are capable of reacting with diethyl acetylenedicarboxylate. It was found that the 4-phenyl thiosemicarbazone derivatives 4a–h reacted with diethyl acetylenedicarboxylate exclusively with the sulfur atom. In this reaction the intermediate 7 undergoes an intramolecular cyclization which leads to the compounds 8a–h.

molecules-19-03068-scheme4_Scheme 4Scheme 4

Preparation of 8a–h with 4-phenyl-3-thiosemicarbazones 4a–h and diethyl acetylenedicarboxylate.

molecules-19-03068-t003_Table 3Table 3

Reactions of 4a–h with diethyl acetylenedicarboxylate.

Compound

Product

Product number

Yield (%)

4a

8a

73

4b

8b

70

4c

8c

76

4d

8d

74

4e

8e

73

4f

8f

75

4g

8g

70

4h

8h

71

Although the two geometrical E- or Z- isomers of 8a–h could be formed in almost equal amounts from the reaction of diethyl acetylenedicarboxylate with 4a–h, 1H-NMR revealed the presence of only one singlet at 6.8 ppm (vinyl proton) indicating that only one E- or Z-isomer was formed. The structures of compound 8b and 8g obtained by X-ray structure analysis confirmed the Z-configuration for the double bond in the 5-position of the thiazolidin-4-ones (Figure 1) [27,28], probably due to the steric effect of the ester group.

Figure 1

ORTEP plots of 8b and 8g.

The chemical structures of the reaction products 8a–h were confirmed by their IR, 1H-NMR, 13C-NMR spectra. The IR spectrum of compound 8a, for example, showed absorptions at 1730, 1692 cm−1 due to the C=O functions of the ester and cyclic amide, respectively. Similarly, bands at 1595–1622 cm−1 are due to the C=N groups. The 1H-NMR spectrum of 8a showed a triplet at δ = 1.28 ppm and a quartet at δ = 4.28 ppm is due to the COOCH2CH3 protons. A singlet at δ = 6.80 ppm is due to C=CH. Aromatic protons appeared as a multiplet at δ = 7.38–7.60 ppm.

3. Experimental3.1. General

Melting points were determined on Büchi B-540 apparatus and are uncorrected. IR spectra were recorded as KBr pellets on a JASCO FT/IR4200 Fourier Transform infrared spectrometer and the reported wavenumbers are given in cm−1. Elemental analyses were carried out at the Spectropole, Faculté des Sciences site Saint-Jérome. 1H-NMR (200 MHz) and 13C-NMR (50 MHz) spectra were recorded on a Bruker ARX 200 spectrometer in CDCl3 or D2O at the Service Inter-Universitaire de RMN de la Faculté de Pharmacie de Marseille. The 1H-NMR chemical shifts were reported as parts per million downfield from tetramethylsilane (Me4Si), and the 13C-NMR chemical shifts were referenced to the solvent peaks: CDCl3 (76.9 ppm) or DMSO-d6 (39.6 ppm). Silica gel 60 (Merck, 230–400 mesh) was used for column chromatography: Thin-layer chromatography was performed with silica gel Merck 60F-254 (0.25 mm layer thickness).

3.2. General Procedure for the Preparation of Compounds 4a–h

To a solution of 4-phenylthiosemicarbazide (2, 1 g, 6 mmol, 1 eq) in ethanol (33 mL) were added the benzaldehyde derivative (6.3 mmol, 1.05 eq) and acetic acid (0.50 mL). The mixture was stirred under reflux for 1–3 h and then cooled to room temperature. After, the solid separated was filtered and recrystallized from ethanol-DMF (3:1) to give compounds 4a–h.

A mixture of compound 4a–h (1.5 mmol, 1 eq), ethyl 2-bromoacetate (0.24 mL, 1.5 mmol) and anhydrous sodium acetate (0.37 g, 4.5 mmol, 3 eq) in ethanol (30 mL) was stirred until reflux; the mixture was stirred under the same conditions till the completion of the reaction (1–3 h). The reaction mixture was left to cool, poured into ice cold water, and the separated solid was ﬁltered, washed with water and recrystallized from a mixture of ethanol-DMF (3:1).

An equimolar mixture of 4a–h (1.5 mmol) and diethyl acetylenedicarboxylate (1.5 mmol) in methanol (20 mL) was refluxed for 1 h. After completion of the reaction, the reaction mixture was allowed to cool to the room temperature. The solid thus separated was collected by filtration and recrystallized using ethanol-DMF mixture.

In conclusion, we have prepared a series of 4-phenyl-3-thiosemicarbazone derivatives from 4-phenyl-3-thiosemicarbazide and various aromatic aldehydes substituted with different electron-donor and -withdrawing groups. In a second step, these 4-phenyl-3-thiosemicarbazone derivatives were reacted with 2-ethyl bromoacetate and diethyl acetylenedicarboxylate, respectively, to afford an original series of highly functionalized thiazolidinone derivatives in good yields. The antiparasitic and antibacterial evaluations of all synthesized compound are under investigation.

Acknowledgments

This work was supported by the CNEPRU (Ministry of Higher Education and Scientific Research Algeria). We express our thanks to Vincent Remusat for recording the 1H and 13C-NMR spectra.

Author Contributions

A.D.; T.T. and P.V. conceived and designed the study. A.B. and O.K. designed the experiments and interpreted the results. A.B.; O.K.; A.D.; T.T. and P.V. wrote the manuscript.

CCDC contains the supplementary crystallographic data of compound 8b for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via http://www.ccdc.cam.ac.uk/data_request/cif.

28.

CCDC contains the supplementary crystallographic data of compound 8g for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via http://www.ccdc.cam.ac.uk/data_request/cif.

Sample Availability: Samples of the compounds 4a–h, 6a–h and 8a–h are available from the authors.